CN113087682A - 苯并噻唑衍生物荧光探针、制备方法、中间体及应用 - Google Patents
苯并噻唑衍生物荧光探针、制备方法、中间体及应用 Download PDFInfo
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- CN113087682A CN113087682A CN202110360984.4A CN202110360984A CN113087682A CN 113087682 A CN113087682 A CN 113087682A CN 202110360984 A CN202110360984 A CN 202110360984A CN 113087682 A CN113087682 A CN 113087682A
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
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Abstract
本发明公开了一种苯并噻唑衍生物荧光探针、制备方法、中间体及应用。本发明所述的苯并噻唑衍生物荧光探针结构式如式(Ⅰ)所示。该荧光探针通过两步合成得到，表现出大的斯托克斯位移，能有效解决因荧光自吸收导致在生物应用方面缺陷。荧光分析表明该化合物可用于水合肼的高灵敏检测，其检测限为0.3μM。本发明具备优良的AIE特性，在细胞中实现对N2H4的精确定位和高灵敏、高选择定量检测，有着良好的应用前景。
Description
技术领域
本发明涉及一种有机小分子生物荧光探针，特别涉及苯并噻唑衍生物荧光探针、制备方法、中间体及应用。
背景技术
近年来，荧光成像技术作为一种新兴分子成像技术发展迅速。荧光成像作为一种高灵敏度、非侵入性的重要生物应用技术，可以监控生命体复杂的生理活动，如病理进化、生物学过程、药物监测等，在生物医学中得到了广泛的应用是分析目标的最佳检测方法之一。有机小分子不仅仅可作为检测目标物的结构，也可以达到靶向癌症细胞，抑制肿瘤生长的作用。有机小分子荧光探针由于其合成可控性、设计方案灵活性和使用简便性等优点成为荧光技术在生物传感器领域的重要组成部分。同时有机小分子的成像能力已成为现阶段临床诊疗过程中的重要辅助手段，在生物医学领域具有广阔的应用前景。
肼(N2H4)是一种非常重要的化学物质，广泛用作喷气发动机和火箭燃料、抗氧化剂、还原剂、催化剂、燃料电池反应物、聚合物交联剂和扩链剂、CO2清除剂、和农药和医药原料。然而，N2H4的使用也因其高毒性而给人类健康和环境安全带来重大风险。此外，尤其是N2H4在任何体积比下都可以很容易地与水混溶形成水合肼，这是不容忽视的。这很容易导致人类和其他生物通过饮用水缓慢摄入N2H4，造成长期损害。高浓度的N2H4或其衍生物可能会引起眼睛、鼻子和喉咙的刺激，暂时性失明、头晕、恶心、肺水肿、昏迷、血液异常、DNA缺陷某些重要器官如肝脏、肺、肾脏和人类中枢神经系统造成损害，甚至是癌症。美国环保局和国际癌症研究机构建议的N2H4最高允许浓度为10ppm(0.31μM)。因此，在活细胞及生物体中监测N2H4具有重要意义，合理设计新颖的荧光探针分子，丰富其荧光成像方式并提高成像性能，已逐渐成为荧光成像技术发展过程中的热点与难点。
传统的有机荧光材料存在一些不足之处，例如：在聚集态或高浓度下存在荧光猝灭现象，斯托克斯位移小，有严重的“自吸收”现象，耐光漂白性能差等。相比传统有机荧光材料，聚集诱导发光荧光材料具有聚集态发射效率高、斯托克斯位移大、光稳定性好、背景噪声低和生物可视化能力强等独特优势，已被成功用作细胞的长期无创和荧光追踪的探针，这为基于影像指导的疾病临床化治疗开辟了新的机遇。AIE发展的20年来，许多AIE探针已成功应用于细胞成像、细胞追踪、体内成像与治疗。尽管如此，用于检测N2H4的AIE型荧光探针仍很缺乏，这类探针有待开发。
发明内容
发明目的：为了解决目前可用于N2H4检测的AIE型荧光探针缺乏的现状，本发明提供了一种苯并噻唑衍生物荧光探针、制备方法中间体和在细胞成像中的应用。
技术方案：本发明所述的一种苯并噻唑衍生物荧光探针，结构式如式(Ⅰ)所示：
该荧光探针的化学名称为(E)-2-(苯并[d]噻唑-2-基)-3-(4'-(二苯氨基)-[1,1'-联苯]-4-基)丙烯腈，分子式为C34H23N3S。
本发明所述的苯并噻唑衍生物荧光探针的制备方法，包括如下步骤：
(a)中间体化合物的合成：将苯并噻唑二乙腈和4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛溶解于有机溶剂中，加碱提供碱性环境，加热回流，反应完全后冷却至室温，有黄色固体析出，过滤，洗涤，得到中间体化合物；
(b)称取步骤(a)中得到的中间体化合物和4-溴-N，N-二苯基苯胺溶于有机溶剂中，以四(三苯基膦)钯作为催化剂，加碱提供碱性环境，N2保护，加热反应，冷却至室温，倒入水中，萃取，将有机相旋干，用乙酸乙酯与石油醚混合溶液洗脱后得苯并噻唑衍生物荧光探针。
优选地，步骤(a)或步骤(b)中，所述的碱选自碳酸钾、哌啶、乙酸铵、三乙胺、六氢吡啶、乙醇钠中的至少一种。
优选地，步骤(a)中，所述的碱为哌啶。步骤(b)中，所述的碱为碳酸钾。
优选地，步骤(a)或步骤(b)中，所述的有机溶剂为甲苯、乙腈、二氯甲烷、二氯乙烷、三氯甲烷、正己烷、四氢呋喃、甲醇、乙醇中的至少一种。
优选地，步骤(a)中，所述的有机溶剂为乙醇。步骤(b)中，所述的有机溶剂为乙醇和甲苯混合溶剂。
优选地，步骤(a)中，所述的有机溶剂为乙醇；步骤(b)中，所述的有机溶剂为乙醇与甲苯的混合溶剂，所述乙醇与甲苯的体积比为1:4-1:8。
最优选地，所述乙醇与甲苯的体积比为1:8。
优选地，步骤(a)中，苯并噻唑二乙腈与4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛的摩尔比为0.8-1.2:0.8-1.2。
优选地，步骤(b)中，用体积比为1：15的乙酸乙酯：石油醚的混合溶液洗脱后得苯并噻唑衍生物荧光探针。
优选地，步骤(a)中，加热回流的温度为75-85℃；步骤(b)中，加热反应的温度为105-115℃。
本发明所述的用于制备所述的苯并噻唑衍生物荧光探针的中间体，结构式如式(Ⅱ)所示：
中间体的名称为；(E)-2-(苯并[d]噻唑-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)丙烯腈。
本发明所述的中间体的制备方法，包括以下步骤：将苯并噻唑二乙腈和4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛溶解于有机溶剂中，加碱提供碱性环境，加热回流，反应完全后冷却至室温，有黄色固体析出，过滤，洗涤，得到中间体化合物。
本发明所述的中间体(E)-2-(苯并[d]噻唑-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)丙烯腈优选的制备方法为：称取苯并噻唑二乙腈和4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛完全溶解于18mL乙醇中，再加入2滴哌啶提供碱性环境，80℃加热回流，用薄层色谱法监测进程，反应完全后冷却至室温，有黄色固体析出，过滤，用冷乙醇洗涤得到目标物。
苯并噻唑二乙腈的结构式为：
本发明所述的苯并噻唑二乙腈与4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛的摩尔比为0.8-1.2:0.8-1.2。
本发明所述的苯并噻唑衍生物荧光探针的优选制备方法为：称取中间体化合物(Ⅱ)(E)-2-(苯并[d]噻唑-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)丙烯腈和4-溴-N，N-二苯基苯胺溶于乙醇和甲苯混合溶剂中，以四(三苯基膦)钯作为催化剂，用碳酸钾溶于水提供碱性环境，N2保护，110℃下反应约24h后，薄层色谱法点板跟踪反应至结束，冷却至室温，倒入水中，用二氯甲烷萃取，将有机相旋干，用乙酸乙酯：石油醚＝1：15洗脱得目标产物。
(E)-2-(苯并[d]噻唑-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)丙烯腈与4-溴-N，N-二苯基苯胺的摩尔比为0.8-1.2:0.8-1.2。
本发明所述的苯并噻唑衍生物荧光探针在N2H4检测中的应用。
本发明所述的苯并噻唑衍生物荧光探针在细胞成像中的应用。
有益效果：(1)本发明首次提供了一类具有AIE性能的苯并噻唑类化合物荧光探针，丰富了N2H4类荧光分子探针的种类，为有机分析和光化学提供了新型的探针分子，可广泛应用于荧光分析或检测领域；(2)本发明的荧光探针通过两步合成得到，表现出大的斯托克斯位移(186nm)，能有效解决因荧光自吸收导致在生物应用方面缺陷；(3)本发明的荧光分子探针实现了对N2H4的高灵敏检测，检测限为0.31μM；(4)本发明的荧光探针分子可以实现在HeLa细胞中对N2H4进行成像。
附图说明
图1为TAB在不同含水量的THF-H2O混合液中的荧光图；
图2为TAB在THF溶液中紫外及荧光图及斯托克斯位移；
图3为TAB的THF溶液对其他不同类型干扰物的荧光图；
图4为TAB的THF溶液对不同浓度N2H4的荧光图；
图5为TAB的THF对N2H4检测动力学图；
图6为TAB在HeLa细胞中对N2H4的成像图。
具体实施方式
实施例1：中间体化合物(E)-2-(苯并[d]噻唑-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)丙烯腈的制备
将苯并噻唑二乙腈(0.3484g，2mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛(0.4642g，2mmol)完全溶解于18mL乙醇中，再加入2滴哌啶提供碱性环境，80℃加热回流，用薄层色谱法监测进程，反应完全后冷却至室温，有黄色固体析出，过滤，用冷乙醇洗涤得到淡黄色固体(纯)产品Ⅱ。
1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.23–8.19(m,1H),8.13–8.06(m,3H),7.89–7.83(m,2H),7.57(dddd,J＝26.2,8.4,7.2,1.3Hz,2H),1.32(s,12H).
实施例2：苯并噻唑衍生物荧光探针(探针分子TAB)(E)-2-(苯并[d]噻唑-2-基)-3-(4'-(二苯氨基)-[1,1'-联苯]-4-基)丙烯腈的制备
称取中间体化合物(E)-2-(苯并[d]噻唑-2-基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)苯基)丙烯腈(0.7039g，1.8mmol)和4-溴-N，N-二苯基苯胺(0.6484g，2mmol)溶于乙醇(5mL)和甲苯(40mL)混合溶剂(乙醇：甲苯体积比为1:8)中，以四(三苯基膦)钯((三苯基膦)钯，0.1040g，5％)作为催化剂，用碳酸钾(0.2487g，1.8mmol)溶于水提供碱性环境，N2保护，110℃下反应约24h后，薄层色谱法点板跟踪反应至结束，冷却至室温，倒入水中，用二氯甲烷萃取，将有机相旋干，用乙酸乙酯：石油醚＝1：15洗脱得到探针TAB。
1H NMR(400MHz,Chloroform-d)δ8.26(d,J＝7.4Hz,1H),8.11(d,J＝8.1Hz,3H),8.03(d,J＝8.0Hz,1H),7.97(d,J＝8.0Hz,1H),7.93(dd,J＝8.4,3.3Hz,1H),7.73(d,J＝8.2Hz,2H),7.62–7.50(m,3H),7.44(dt,J＝17.3,8.2Hz,2H),7.33(t,J＝7.7Hz,3H),7.14(dt,J＝29.0,7.2Hz,7H).ESI-MS m/z:[probe]-calcd for C34H23N3S 505.64；Found506.16.
实施例3：探针分子TAB在不同含水量的THF-H2O混合液中的荧光图
测试仪器：日立F7100型分子荧光光谱仪。
实验方法为：将实施例2制得的探针分子TAB溶解于THF中得到1mM的探针母液，常温保存。用探针母液分别配制成0％,10％,20％，30％,40％,50％,60％,70％,80％,90％,95％含水量的THF-H2O混合液(配制方法：加入相同量的探针母液，然后在加入对应比例的H2O之前用溶剂补至总体积一致，最后加H2O，得到对应含水量的THF-H2O混合液)，浓度均为0.01mM。
测量时分别移取3mL不同含水量的THF-H2O混合液到1cm比色皿中先后进行荧光光谱测试，如图1所示，当含水量由0％增加到60％时，由于扭曲的分子内电荷转移(TICT)，荧光强度逐渐减小；然而，当加入水达到70-90％时，由于水的诱导聚集，TAB的发射信号持续增强，表现出典型的AIE特征。当含水量为95％时，TAB容易沉淀，因此观察到相对较差的发射性能。故选用90％含水量的探针溶液用于后续的TAB的各类性能测试。
实施例4：探针分子C-BH的紫外吸收光谱及荧光光谱性质测试
测试仪器：PE 950s型紫外光谱仪，日立F7100型分子荧光光谱仪。
实验方法为：将实施例2制得的探针分子TAB溶解于THF溶液中得到1mM的探针母液，常温保存。实验测定中用THF和H2O将溶液稀释成0.01mM的标准液进行测试(HF-H2O，90％含水量)。
测量时移取3mL探针的THF溶液到1cm比色皿中先后进行紫外吸收光谱及荧光光谱测试，如图2所示。结果表明：探针TAB最强紫外吸收峰出现在432nm左右，荧光发射峰出现在618nm左右，斯托克位移达到186nm。这种大的斯托克位移，可以有效的克服因荧光自吸收而在生命体中难以应用的缺陷，实现探针在生命体中的应用。
实施例5：探针分子TAB对其他干扰离子的荧光图
测试仪器：日立F100型分子荧光光谱仪。
实验方法为：将实施例2制得的探针分子TAB溶解于THF中得到1mM的探针母液，常温保存。N2H4、PbCl2、ZnCl2、Co(NO3)2、CaCl2、KCl、AgNO3、FeCl3、FeSO4、MgSO4、CH3COONa、Na2CO3、KHSO4、KOH、Hcy、Cys用二次水配置成0.01M母液。实验测定中将探针溶液稀释成1μM的标准溶液(HF-H2O，90％含水量)进行测试。测量时移取3mL探针的THF溶液到1cm比色皿中分别滴加40μM的N2H4、PbCl2、ZnCl2、Co(NO3)2、CaCl2、KCl、AgNO3、FeCl3、FeSO4、MgSO4、CH3COONa、Na2CO3、KHSO4、KOH、Hcy、Cys进行荧光测试，未加离子溶液的探针作为对照组。结果如图3所示。结果表明：探针TAB对N2H4表现出明显的荧光增强现象，而对于一些生物体内常见的金属阳离子和酸根阴离子以及高半胱氨酸和半胱氨酸几乎没有什么影响，进一步说明探针TAB具有优异的选择性，能够应用于生物体内。
实施例6：TAB的THF溶液对N2H4的定量分析图
测试仪器：日立F7100型分子荧光光谱仪。
实验方法为：将实施例2制得的探针分子TAB溶解于THF中得到1mM的探针母液，常温保存。N2H4用二次水配置成0.15M母液，实验测定中将探针溶液稀释成10μM的标准溶液(HF-H2O，90％含水量)进行测试。
采用标准加入法测试探针分子对N2H4的荧光响应，移取3mL的探针母液(10μM)至比色皿中，每次加入0.5μL的N2H4检测荧光强度变化，N2H4含量加到30μM不再继续加入，如图4所示，随着N2H4含量的增加，在418nm处的荧光峰强度不断增强，因此，该探针对N2H4有较高的灵敏度，可用于生物体内微量N2H4的检测。
从图4得到N2H4的检测极限为0.31μmol。检测极限的计算方法为：根据公式LOD＝3σ/k，其中σ是空白溶液(不添加N2H4)测量的标准差，k是强度与浓度(N2H4)曲线的斜率，σ是由以下公式计算所得：
实施例7：探针分子TAB在N2H4存在下的动力学实验图
测试仪器：日立F7100型分子荧光光谱仪。
实验方法为：将实施例2制得的探针分子TAB溶解于THF中得到1mM的探针母液，常温保存。N2H4用二次水配置成0.15M母液。实验测定中将溶液稀释成10μM的标准溶液(HF-H2O，90％含水量)进行测试。
移取3mL的探针母液(10μM)至比色皿中，设置荧光激发波长为350nm，分别测试探针，探针+N2H4溶液在不同的时间(0分钟，2分钟，4分钟，6分钟，8分钟，10分钟，15分钟，20分钟，30分钟,40分钟，50分钟，60分钟，70分钟，80分钟)荧光强度的变化，如图5所示。实验结果表明，开始探针溶液的荧光强度随时间的增加而增强，探针+N2H4在60min内荧光强度达到最高值，后荧光强度趋于稳定。
实施例8：探针分子TAB在HeLa细胞中对N2H4的成像研究
实验方法为：将实施例2制得的探针分子TAB溶解于THF中得到1mM的探针母液，常温保存。实验测定中用THF和H2O将溶液稀释成0.01mM的标准液(HF-H2O，90％含水量)进行测试。
为了证明探针在生物系统的实际应用，在共聚焦荧光显微镜下对细胞进行了在不同pH值下的生物荧光成像实验。将HeLa细胞接到培养皿中在37℃条件下培养24h，然后将TAB标准液(10μM)加入到培养皿中，加入不同浓度的N2H4(15，30，60μM)继续孵育1小时后进行荧光成像，如图6所示，图6中，上半部分的图(图A1、图B1、图C1、图D1)为激光共聚焦的红色通道和蓝色通道叠加的图，下半部分的图(图A2、图B2、图C2、图D2)图为明场的图。实验结果表明探针分子TAB在随着N2H4浓度增加，荧光在不断增强。这些结果表明，探针TAB可以作为检测细胞内N2H4的荧光标签进入细胞，因而具有在生物体内检测N2H4的潜力。
Claims (10)
1.一种苯并噻唑衍生物荧光探针，其特征在于，结构式如式(Ⅰ)所示：
2.一种如权利要求1所述的苯并噻唑衍生物荧光探针的制备方法，其特征在于，包括如下步骤：
(a)中间体化合物的合成：将苯并噻唑二乙腈和4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛溶解于有机溶剂中，加碱提供碱性环境，加热回流，反应完全后冷却至室温，有黄色固体析出，过滤，洗涤，得到中间体化合物；
(b)称取步骤(a)中得到的中间体化合物和4-溴-N，N-二苯基苯胺溶于有机溶剂中，以四(三苯基膦)钯作为催化剂，加碱提供碱性环境，N2保护，加热反应，冷却至室温，倒入水中，萃取，将有机相旋干，用乙酸乙酯与石油醚混合溶液洗脱后得苯并噻唑衍生物荧光探针。
3.根据权利要求2所述的苯并噻唑衍生物荧光探针的制备方法，其特征在于，步骤(a)或步骤(b)中，所述的碱选自碳酸钾、哌啶、乙酸铵、三乙胺、六氢吡啶、乙醇钠中的至少一种。
4.根据权利要求2所述的苯并噻唑衍生物荧光探针的制备方法，其特征在于，步骤(a)或步骤(b)中，所述的有机溶剂为甲苯、乙腈、二氯甲烷、二氯乙烷、三氯甲烷、正己烷、四氢呋喃、甲醇、乙醇中的至少一种。
5.根据权利要求2所述的苯并噻唑衍生物荧光探针的制备方法，其特征在于，步骤(a)中，所述的有机溶剂为乙醇；步骤(b)中，所述的有机溶剂为乙醇与甲苯的混合溶剂，所述乙醇与甲苯的体积比为1:4-1:8。
6.根据权利要求2所述的苯并噻唑衍生物荧光探针的制备方法，其特征在于，步骤(a)中，加热回流的温度为75-85℃；步骤(b)中，加热反应的温度为105-115℃。
7.一种制备如权利要求1所述的苯并噻唑衍生物荧光探针的中间体，其特征在于，结构式如式(Ⅱ)所示：
8.一种如权利要求7所述的中间体的制备方法，其特征在于，包括以下步骤：将苯并噻唑二乙腈和4-(4,4,5,5-四甲基-1,3,2-二氧杂戊烷-2-基)苯甲醛溶解于有机溶剂中，加碱提供碱性环境，加热回流，反应完全后冷却至室温，有黄色固体析出，过滤，洗涤，得到中间体化合物。
9.一种如权利要求1所述的苯并噻唑衍生物荧光探针在N2H4检测中的应用。
10.一种如权利要求1所述的苯并噻唑衍生物荧光探针在细胞成像中的应用。
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| CN115260120A (zh) * | 2022-04-26 | 2022-11-01 | 安徽工程大学 | 一种用于联氨特异性检测的esipt荧光化合物及其制备方法和应用 |
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| CN115260120B (zh) * | 2022-04-26 | 2023-06-02 | 安徽工程大学 | 一种用于联氨特异性检测的esipt荧光化合物及其制备方法和应用 |
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